The present invention concerns therapy for a variety of maladies, including at least spinal cord injury and intraventricular hemorrhage.
Spinal Cord Injury
Acute spinal cord injury (SCI) results in physical disruption of spinal cord neurons and axons leading to deficits in motor, sensory, and autonomic function. SCI is a debilitating neurological disorder common in young adults that often requires life-long therapy and rehabilitative care, placing significant burdens on healthcare systems. Although many patients exhibit neuropathologically and clinically complete cord injuries following SCI, many others have neuropathologically incomplete lesions (Hayes and Kakulas, 1997; Tator and Fehlinds, 1991) giving hope that proper treatment to minimize “secondary injury” may reduce the functional impact.
The concept of secondary injury in SCI arises from the observation that the lesion expands and evolves over time (Tator and Fehlings, 1991; Kwon et al., 2004). Whereas primary injured tissues are irrevocably damaged at the time of impact, tissues that are destined to become “secondarily” injured are considered to be potentially salvageable. Older observations based on histological studies that gave rise to the concept of lesion-evolution have been confirmed with non-invasive MRI (Bilgen et al., 2000).
Several mechanisms of secondary injury have been postulated, including ischemia/hypoxia, oxidative stress and inflammation, all of which have been considered to be responsible for the devastating process termed “progressive hemorrhagic necrosis” (PHN) (Tator and Fehlings, 1991; Nelson et al., 1977; Tator, 1991; Fitch et al., 1999; Tator and Koyanagi, 1997). PHN is a mysterious condition, first recognized over three decades ago, that has thus far eluded understanding and treatment. Shortly after injury (10-15 min), a small hemorrhagic lesion involving primarily the capillary-rich central gray matter is observed, but over the following 3-24 h, petechial hemorrhages emerge in more distant tissues, eventually coalescing into the characteristic lesion of hemorrhagic necrosis (Balentine, 1978; Kawata et al., 1993). The white matter surrounding the hemorrhagic gray matter shows a variety of abnormalities, including decreased hematoxylin and eosin staining, disrupted myelin, and axonal and periaxonal swelling. White matter lesions extend far from the injury site, especially in the posterior columns (Tator and Koyanagi, 1997). The evolution of hemorrhage and necrosis has been referred to as “autodestruction”. PHN results in loss of vital spinal cord tissue and, in some species including humans, leads to post-traumatic cystic cavitation surrounded by glial scar tissue.
The mechanism responsible for PHN is not known. Tator and Koyanagi (1997) speculated that obstruction of small intramedullary vessels by the initial mechanical stress or secondary injury might be responsible for PHN, whereas Kawata and colleagues (Kawata et al., 1993) attributed the progressive changes to leukocyte infiltration around the injured area leading to plugging of capillaries. Given that petechial hemorrhages, the pathognomonic feature of PHN, form as a result of catastrophic failure of vascular integrity, damage to the endothelium of spinal cord capillaries and postcapillary venules has long been regarded as a major factor in the pathogenesis of PHN (Nelson et al., 1977; Griffiths et al., 1978; Kapadia, 1984). However, no molecular mechanism for progressive dysfunction of endothelium has been identified.
The sulfonylurea receptor-1 (SUR1)-regulated NCCa-ATP channel is a non-selective cation channel that is not constitutively expressed, but is transcriptionally up-regulated in astrocytes and neurons following an hypoxic or ischemic insult (Chen and Simard, 2001; Chen et al., 2003; Simard et al., 2006). The channel is inactive when expressed, but becomes activated when intracellular ATP is depleted, with activation leading to cell depolarization, cytotoxic edema and oncotic cell death. Block of the channel in vitro by the sulfonylurea, glibenclamide, prevents cell depolarization, cytotoxic edema and oncotic cell death induced by ATP depletion. In rodent models of ischemic stroke, treatment with glibenclamide results in significant improvements in edema, lesion volume and mortality (Simard et al., 2006). In humans with diabetes mellitus, use of sulfonylureas before and during hospitalization for stroke is associated with significantly better stroke outcomes (Kunte et al., 2007).
Intra-Axial Hemorrhage
Intra-axial hemorrhage is characterized by bleeding within the brain itself. Intraparenchymal or intraventricular hemorrhages are types of intra-axial hemorrhage.
Intraventricular Hemorrhage (IVH)
Intraventricular Hemorrhage (IVH), a bleeding from fragile blood vessels in the brain, is a significant cause of morbidity and mortality in premature infants and may have include, for example, death, shunt-dependent hydrocephalus, and life-long neurological consequences such as cerebral palsy, seizures, mental retardation, and other neurodevelopmental disabilities. Neurological sequelae include shunt-dependent hydrocephalus, seizures, neurodevelopmental disabilities, and cerebral palsy. The vasculature is especially fragile in preterm infants, particularly those born more than 8 weeks early, i.e., before 32 weeks of gestation. IVH is more commonly seen in extremely premature infants; its incidence is over 50% in preterm infants with birth weight less than 750 grams, and up to 25% in infants with birth weight less than 1000 to 1500 grams.
IVH encompasses a wide spectrum of intra-cranial vascular injuries with bleeding into the brain ventricles, a pair of C-shaped reservoirs, located in each half of the brain near its center, that contain cerebrospinal fluid. Bleeding occur in the subependymal germinal matrix, a region of the developing brain located in close proximity to the ventricles. Within the germinal matrix, during fetal development, there is intense neuronal proliferation as neuroblasts divide and migrate into the cerebral parenchyma. This migration is about complete by about the 24th week of gestation, although glial cells can still be found within the germinal matrix until term. The germinal matrix undergoes rapid involution from the 26th to the 32nd week of gestation, at which time regression is nearly complete, as glial precursors migrate out to populate the cerebral hemispheres.
Supporting this intense cell differentiation and proliferation activity there is a primitive and fragile capillary network. These vessels have thin walls for their relatively large size, lack a muscularis layer, have immature interendothelial junctions and basal laminae, and often lack direct contact with perivascular glial structures, suggesting diminished extravascular support. It is in this fragile capillary network where IVH originates. When a fetus is born prematurely, the infant is suddenly thrust from a well-controlled, protective environment into a stimulating, hostile one. Because of this physiologic stress and shock, the infant may lose the ability to regulate cerebral blood flow and may suffer alterations in blood flow and pressure and in the amounts of substances dissolved in the blood such as oxygen, glucose and sodium. The fragile capillaries may, and often do, rupture.
The severity of the condition depends on the extent of the vascular injury. There are four grades, or stages, of IVH as can be seen using ultrasound or brain computer tomography. Grade I IVH, the less severe stage, involves bleeding in the subependymal germinal matrix, with less than 10% involvement of the adjacent ventricles. Grade II IVH results when 10 to 40% of the ventricles are filled with blood, but without enlargement of the ventricles. Grade III IVH involves filling of over 50% of the ventricles with blood, with significant ventricular enlargement. In Grade IV IVH, the bleeding extends beyond the intraventricular area into the brain parenchyma (intraparenchymal hemorrhage).
The major complications of IVH relate to the destruction of the cerebral parenchyma and the development of posthemorrhagic hydrocephalus. Following parenchymal hemorrhages (Grade IV IVH), necrotic areas may form cysts that can become contiguous with the ventricles. Cerebral palsy is the primary neurological disorder observed in those cases, although mental retardation and seizures may also occur. In addition, infants affected with Grade III to IV IVH may develop posthemorrhagic hydrocephalus, a condition characterized by rapid growth of the lateral ventricles and excessive head growth within two weeks of the hemorrhage. Likely causes are obstruction of the cerebrospinal fluid conduits by blood clots or debris, impaired absorption of the cerebrospinal fluid at the arachnoid villi, or both. Another form of the hydrocephalus condition may develop weeks after the injury. In this case the likely cause is obstruction of the cerebrospinal fluid flow due to an obliterative arachnoiditis in the posterior fossa.
Several trials were conducted in the 1980s and 1990s to evaluate prophylactic use of phenobarbitone in preterm infants to reduce the risk of IVH, however, no statistical significance was observed (Postnatal phenobarbitone for the prevention of intraventricular hemorrhage in preterm infants, Whitelaw et al., 2000; and Bedard M P, Shankaran S, Slovis T L, Pantoja A, Dayal B. Poland R L. Effect of prophylactic phenobarbital on intraventricular hemorrhage in high-risk infants. Pediatrics 1984; 73:435-9.). Other pharmacological interventions have been assessed, such as indomethacin (Fowlie 1999), but without substantial clinical impact and IVH remains a problem. (Whitelaw A, Placzek M, Dubowitz L, Lary S, Levene M. Phenobarbitone for prevention of periventricular haemorrhage in very low birth-weight infants. A randomised double-blind trial. Lancet 1983; ii:1168-70.).
Extra-Axial Hemorrhage
Extra-axial hemorrhage is characterized by bleeding that occurs within the skull but outside of the brain tissue. Epidural hemorrhage, subdural hemorrhage and subarachnoid hemorrhage are types of extra-axial hemorrhage.
Subarachnoid Hemorrage (SAH)
SAH, like intraparenchymal hemorrhage, may result from trauma (physical or physiological) or from ruptures of aneurysms or arteriovenous malformations, or a combination thereof. SAH often indicates the presence of blood within the subarachnoid space, blood layering/layered into the brain along sulci and fissures, or blood filling cisterns (such as the suprasellar cistern because of the presence of the vessels of the circle of Willis and their branchpoints within that space). The classic presentation of subarachnoid hemorrhage is the sudden onset of a severe headache. This can be a very dangerous entity, and requires emergent neurosurgical evaluation, and sometimes urgent intervention. In the United States, the annual incidence of nontraumatic SAH is about 6-25 per 100,000. Internationally, incidences have been reported but vary to 2-49 per 100,000.
Unlike ischemic stroke, in SAH the entire cortex bathed in blood is at risk from hemotoxicity-related inflammation. Also, hemotoxicity-related inflammation is potentially more amenable to treatment than ischemic stroke because it develops relatively slowly, compared to rapid loss of penumbral tissues in ischemia. At present, treatments for edema are limited because underlying molecular mechanis are not well understood, and treatments aimed at mechanism that have been implicated (Park et al., 2004) are not yet available. Therefore, the present invention fulfills a long-standing need in the art by providing a treatment for SAH predicated on ameliorating (or otherwise inhibiting) post-SAH hemotoxicity-related inflammation.
The present invention provides a solution for a long-felt need in the art to treat progressive hemorrhagic necrosis following spinal cord injury and to treat IVH, traumatic brain injury, and subarachnoid hemorrhage. for example.